Vascular Signal Transduction Mechanisms

There are several signal transduction mechanisms that modulate intracellular calcium concentration and therefore the state of vascular tone. Two different mechanisms will be described here: 1) G-protein-coupled pathway, and 2) the nitric oxide-cGMP pathway.

Gs-Protein Coupled Signal Transduction

Like heart muscle, the Gs-protein coupled pathway in smooth stimulates stimulates adenylyl cyclase (AC), which catalyzes the formation of cAMP.  Unlike the heart, however, an increase in cAMP in vascular smooth muscle causes reduced contraction (i.e., relaxation). The reason for this opposite effect is that that calcium-calmodulin activates myosin light chain kinase (MLCK), which phosphorylates myosin and causes contraction; however, MLCK is inhibited by cAMP.

The Gs-protein is coupled to several important receptors that bind vasodilator substances, among which are β₂-adrenoceptors (bind to β₂-agonists such as epinephrine and isoproterenol), A₂ purinergic receptors (bind to adenosine), and IP receptors (bind prostacyclin, PGI₂).

IP₃- Coupled Signal Transduction

The phosphatidylinositol pathway in vascular smooth muscle is similar to that found in the heart. Alpha-agonists (e.g., norepinephrine) acting through α₁-adrenoceptors, angiotensin II (AII) acting through AT₁ receptors, endothelin-1 (ET-1) acting through ET_A receptors, vasopressin acting through V₁ receptors, and acetylcholine acting through muscarin receptors activate phospholipase C (PL-C) causing the formation of inositol triphosphate (IP₃) from phosphatidylinositol (PIP₂). The IP₃ then stimulates the sarcoplasmic reticulum (SR) to release calcium. The formation of diacylglycerol (DAG) activates protein kinase C (PK-C), which can also contribute to vascular smooth muscle contraction via protein phosphorylation.

cGMP-Coupled Signal Transduction

A third mechanism that is very important in regulating vascular smooth muscle tone is the nitric oxide (NO)-cGMP system. Vascular endothelial cells normally produce NO, which diffuses from endothelial cells to adjacent smooth muscle cells where it activates guanylyl cyclase leading to increased formation of cGMP and vasodilation. The precise mechanisms by which cGMP relaxes vascular smooth muscle is unclear; however, cGMP can activate a cGMP-dependent protein kinase, inhibit calcium entry into the vascular smooth muscle, activate K⁺ channels, and decrease IP₃.

Acetylcholine (ACh), whether released by cholinergic autonomic nerves or exogenously administered, binds to muscarinic receptors on the vascular endothelium (muscarinic receptors in coronary vessels), which stimulates the formation and release of NO as described above to produce vasodilation. Certain antihypertensive and antianginal drugs are called nitrodilators because they release NO, and thereby mimic the effect of endothelial produced NO.

Revised 10/25/2012